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The abnormal activity of PP2A, a dominant member of type 2A serine/threonine protein phosphatase, has been implicated in the development of Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB). PP2A is a holoenzyme, and protein methylation of the catalytic subunit, PP2Ac, alters the complex composition. A decrease in PP2Ac methylation levels has been reported in AD and DLB. Aging is the most common risk factor for AD and DLB, but the relationship between aging and PP2A has not been studied in detail. Cynomolgus monkey show increased phosphorylation levels of tau and α-synuclein with aging. In this study, we investigated the alterations in the PP2A activity regulation with aging in monkey brains from 2 to 43 years of age using fractionated proteins. We found that type 2A protein phosphatase activity decreased with aging in cytoplasmic and nuclear-soluble fractions. PP2Ac methylation level was decreased in cytoplasmic and sarkosyl-insoluble fractions. A principal component analysis using PP2Ac, demethylated PP2Ac and PP2A methylesterase PME-1 levels in cytoplasmic and nuclear-soluble fractions as attributes showed that aged monkeys were in the same cluster. Our results show that brain aging in cynomolgus monkeys is closely related to changes in PP2A methylation.

SET/I2PP2A is a multifunctional protein that acts as an intrinsic inhibitor of the tumour suppressor protein phosphatase 2A and as a histone chaperone. Increased SET levels have been observed in various cancers; however, the underlying molecular mechanisms remain unclear. In this study, we found that SET protein accumulates with the increasing density of cultured cells. This phenomenon was observed not only in cancer cell lines but also in non-cancer cell lines. The mRNA levels of SET were not affected by the cell density. Proteasome inhibition decreased SET levels, whereas autophagy inhibition led to SET accumulation, indicating the involvement of autophagy. The mRNA and protein expression of SETBP1, which stabilizes the SET protein, increased with cell density. The decrease in SET level due to the loss of SETBP1 was more pronounced in wild-type cells than that in autophagy-deficient cells. These results have revealed a mechanism underlying the regulation of SET level, wherein increased cell density induces SETBP1 expression and protects SET from autophagy.

Understanding the molecular mechanism of neuronal differentiation is important to overcome the incurable diseases caused by nervous system damage. Neurite outgrowth is prerequisite for neuronal differentiation and regeneration, and cAMP response element-binding protein (CREB) is one of the major transcriptional factors positively regulating this process. Neuronal differentiation stimuli activate mammalian target of rapamycin (mTOR) complex 2 (mTORC2)/Akt signalling to phosphorylate CREB; however, the precise molecular mechanism of this event has not been fully understood. In this manuscript, we show that neuronal differentiation stimuli increased a protein level of protein phosphatase 6 (PP6), a member of type 2A Ser/Thr protein phosphatases. PP6 knockdown suppressed mTORC2/Akt/CREB signalling and results in failure of neurite outgrowth. SIN1 is a unique component of mTORC2 that enhances mTORC2 activity towards Akt when it is in dephosphorylated form. We found PP6 knockdown increased SIN1 phosphorylation. These data suggest that PP6 may positively regulate neurite outgrowth by dephosphorylating SIN1 to activate mTORC2/Akt/CREB signalling.

Gut-associated sepsis is a major problem in patients undergoing abdominal radiation therapy; the majority of pathogens causing this type of sepsis are translocated from the gut microbiota. While treating sepsis, bacterial clearance must be achieved to ensure patient survival, and the hepatic immune response is responsible for this process. In particular, Kupffer cells play a crucial role in the hepatic immune response against infectious agents. Recently, two populations of Kupffer cells have been described: liver-resident macrophages (Mϕ) (F4/80+CD11b–CD68+ cells) and hepatic Mϕ derived from circulating monocytes (F4/80+CD11b+CD68– cells). We examined the properties of both types of hepatic Mϕ obtained from irradiated and normal mice and their role in sepsis. Hepatic F4/80+CD11b–CD68+ cells from both normal and irradiated mice did not show any antibacterial activity. However, F4/80+CD11b+CD68– cells from normal mice behaved as effector cells against sepsis by Enterococcus faecalis, although those from irradiated mice lost this ability. Moreover, hepatic F4/80+CD11b+CD68– cells from normal infected mice were shown to be IL-12+IL-10–CD206–CCL1– (considered M1Mϕ), and hepatic F4/80+CD11b–CD68+ cells from the same mice were shown to be IL-12–IL-10+CD206+CCL1– (considered M2aMϕ). When normal mice were exposed to radiation, hepatic F4/80+CD11b+CD68– cells altered their phenotype to IL-12–IL-10+CD206–CCL1+ (considered M2bMϕ), independent of infection, but hepatic F4/80+CD11b–CD68+ cells remained IL-12–IL-10+CD206+CCL1– (M2aMϕ). In addition, hepatic F4/80+CD11b+CD68– cells from irradiated mice acquired antibacterial activity upon treatment with CCL1 antisense oligodeoxynucleotides. Therefore, the characteristics of hepatic F4/80+CD11b+CD68– cells play a key role in the antibacterial response against gut-associated sepsis.

The costs of clean-energy technologies are currently very high and their adoption in buildings is voluntary. This study evaluated strategies for improving the cost performance of photovoltaic (PV) electricity applied in buildings in Nigeria using a questionnaire survey involving 415 targets. The efficacy of each strategy and consensus in respondents’ perceptions were determined using Fuzzy Set Theory and Kruskal–Wallis tests. The top four strategies for achieving PV-cost reduction are mandating green buildings, standardization of building designs and PV components, facilitating import licensing and massive public education. Developing these strategies to improve the PV value chain will increase the supply capacity of clean energy in emerging markets.

Background Lenvatinib is used for unresectable hepatocellular carcinoma (u-HCC) as first-line, as well as second- and third-line therapy in Japan. We evaluated the therapeutic efficacy of newly developed ramucirumab when given after lenvatinib for post-progression treatment. Methods Of 385 patients with u-HCC and treated with lenvatinib at 16 different institutions in Japan between May 2018 and January 2020, 28 who received ramucirumab as the next treatment were enrolled and therapeutic responses were evaluated in a retrospective manner. Results The median age of the 28 patients given ramucirumab was 70 years and the median albumin-bilirubin score was −2.19. Of the 28 patients, 23 were male, 21 were classified as Child–Pugh A and 7 as Child–Pugh B, and 25 were Barcelona Clinic Liver Cancer Stage C. Ramucirumab was given as second-line therapy in 14, third-line in 9, and fourth-line in 5. Therapeutic response was obtained in only 26 patients; the objective response rate was 3.8% (1/26) and the disease-control rate was 42.3% (11/26), with a median period to progression of 2.0 months. The reasons for discontinuation of ramucirumab were progression of disease in 16 and Grade 3 adverse events (gastrointestinal bleeding, ascites) in 2. Conclusions The anticipated therapeutic efficacy of ramucirumab for post-progression treatment following lenvatinib was not seen in our early experience.

Bone marrow-derived mesenchymal stem cells (BM-MSCs) are multipotent stem cells with ability to self-replicate and differentiate into mesodermal derivatives, such as adipocytes and osteoblasts. BM-MSCs are a critical component of the tumour microenvironment. They support tumour progression by recruiting additional BM-MSCs and by differentiating into myofibroblasts (also called cancer-associated fibroblasts). Protein phosphatase 2A (PP2A) is an essential serine/threonine protein phosphatase that regulates a broad range of cellular signalling. PP2A forms a heterotrimer to dephosphorylate specific substrates. The reversible methylesterification (methylation) of Leu309 in the catalytic subunit of PP2A (PP2Ac) regulates biogenesis of the PP2A holoenzyme. It is unknown whether the methylation of PP2Ac plays a role in BM-MSC differentiation. Our experiments determined that protein levels of PP2A subunits and PP2A methyltransferase (LCMT-1) are significantly altered during differentiation. PP2Ac methylation levels in BM-MSCs decrease over time in response to an adipogenic differentiation stimulus. However, blockage of PP2A demethylation using the PP2A dimethyl-esterase inhibitors enhanced adipocyte differentiation. This suggests that PP2Ac demethylation is involved in adipocyte differentiation resistance. The results of our study provide a greater understanding of the regulation of BM-MSCs differentiation by PP2A holoenzyme.

W$\, 51\,$A is one of the most active star-forming regions in the Milky Way, and includes copious amounts of molecular gas with a total mass of ${\sim }6\times 10^{5}\, M_{\odot }$. The molecular gas has multiple velocity components over ∼20 km s−1, and interactions between these components have been discussed as the mechanism that triggered the massive star formation in W$\, 51\,$A. In this paper, we report on an observational study of the molecular gas in W$\, 51\,$A using the new 12CO, 13CO, and C18O (J = 1–0) data covering a 1${^{\circ}_{.}}$4 × 1${^{\circ}_{.}}$0 area of W$\, 51\,$A obtained with the Nobeyama 45 m telescope at 20′ resolution. Our CO data resolved four discrete velocity clouds with sizes and masses of ∼30 pc and 1.0–$1.9\times 10^{5}\, M_{\odot }$ around radial velocities of 50, 56, 60, and 68 km s−1. Toward the central part of the Hii region complex G49.5−0.4 in W$\, 51\,$A, in which the bright stellar clusters IRS 1 and IRS 2 are located, we identified four C18O clumps having sizes of ∼1 pc and column densities of higher than 1023 cm−2, which are each embedded within the four velocity clouds. These four clumps are concentrated within a small area of 5 pc, but show a complementary distribution on the sky. In the position–velocity diagram, these clumps are connected with each other by bridge features having weak intensities. The high intensity ratios of 13CO (J = 3–2)$/$(J = 1–0) also indicate that these four clouds are associated with the Hii regions, including IRS 1 and IRS 2. We also reveal that, in the other bright Hii region complex G49.4−0.3, the 50, 60, and 68 km s−1 clouds show a complementary distribution, with two bridge features connecting between the 50 and 60 km s−1 clouds and the 60 and 68 km s−1 clouds. An isolated compact Hii region G49.57−0.27 located ∼15 pc north of G49.5−0.4 also shows a complementary distribution and a bridge feature. The complementary distribution on the sky and the broad bridge feature in the position–velocity diagram suggest collisional interactions among the four velocity clouds in W$\, 51\,$A. The timescales of the collisions can be estimated to be several 0.1 Myr as crossing times of the collisions, which are consistent with the ages of the Hii regions measured from the sizes of the Hii regions with the 21 cm continuum data. We discuss a scenario of cloud–cloud collisions and massive star formation in W$\, 51\,$A by comparing these with recent observational and theoretical studies of cloud–cloud collision.

Sh2-48 is a Galactic HII region located at 3.8 kpc with an O9.5-type star identified at its center. As a part of the FOREST Unbiased Galactic plane Imaging survey using the Nobeyama 45-m telescope (FUGIN) project, we obtained the CO J=1-0 dataset for a large area of Sh2-48 at a spatial resolution of 21"(~0.4 pc), which we used to find a molecular cloud with a total molecular mass of ~3.8x10^4 Mo associated with Sh2-48. The molecular cloud has a systematic velocity shift within a velocity range ~42-47 km/s . On the lower velocity side the CO emission spatially corresponds with the bright 8 {\mu}m filament at the western rim of Sh2-48, while the CO emission at higher velocities is separated at the eastern and western sides of the 8{\mu}m filament. This velocity change forms V-shaped, east-west-oriented feature on the position-velocity diagram. We found that these lower and higher-velocity components are, unlike the infrared and radio continuum data, physically associated with Sh2-48. To interpret the observed V-shaped velocity distribution, we assessed a cloud-cloud collision scenario and found from a comparison between the observations and simulations that the velocity distribution is an expected outcome of a collision between a cylindrical cloud and a spherical cloud, with the cylindrical cloud corresponding to the lower-velocity component, and the two separated components in the higher-velocity part interpretable as the collision-broken remnants of the spherical cloud. Based on the consistency of the ~1.3Myr estimated formation timescale of the HII region with that of the collision, we concluded that the high-mass star formation in Sh2-48 was triggered by the collision., Comment: 26 pages, 18 figures, Accepted for publications in the PASJ

Group A1 heat shock transcription factors (HsfA1s) are the master regulators of the heat stress response (HSR) in plants. Upon heat shock, HsfA1s trigger a transcriptional cascade that is composed of many transcription factors. Despite the importance of HsfA1s and their downstream transcriptional cascade in the acquisition of thermotolerance in plants, the molecular basis of their activation remains poorly understood. Here, domain analysis of HsfA1d, one of several HsfA1s in Arabidopsis thaliana, demonstrated that the central region of HsfA1d is a key regulatory domain that represses HsfA1d transactivation activity through interaction with HEAT SHOCK PROTEIN70 (HSP70) and HSP90. We designated this region as the temperature-dependent repression (TDR) domain. We found that HSP70 dissociates from HsfA1d in response to heat shock and that the dissociation is likely regulated by an as yet unknown activation mechanism, such as HsfA1d phosphorylation. Overexpression of constitutively active HsfA1d that lacked the TDR domain induced expression of heat shock proteins in the absence of heat stress, thereby conferring potent thermotolerance on the overexpressors. However, transcriptome analysis of the overexpressors demonstrated that the constitutively active HsfA1d could not trigger the complete transcriptional cascade under normal conditions, thereby indicating that other factors are necessary to fully induce the HSR. These complex regulatory mechanisms related to the transcriptional cascade may enable plants to respond resiliently to various heat stress conditions.

著者人数: 18名, Accepted: 2017-11-20, 資料番号: SA1180041000

著者人数: 17名, Accepted: 2017-10-25, 資料番号: SA1180039000

High-mass star formation is an important step which controls galactic evolution. GM 24 is a heavily obscured star cluster including a single O9 star with more than $\sim$100 lower mass stars within a 0.3 pc radius toward $(l,b)\sim$ (350.$^{\circ}$5, 0.$^{\circ}$96), close to the Galactic min-starburst NGC 6334. We found two velocity components associated with the cluster by new observations of $^{12}$CO $J=$ 2-1 emission, whereas the cloud was previously considered to be single. We found the distribution of the two components of $5$ km s$^{-1}$ separation shows complementary distribution which fits well with each other, if a relative displacement of 3 pc is applied along the Galactic plane. A position-velocity diagram of the GM 24 cloud is explained by a model based on the numerical simulations of two colliding clouds, where an intermediate velocity component created by collision is taken into account. We estimate the collision time scale to be $\sim$Myr in projection of a relative motion titled to the line of sight by 45 degrees. The results lend further support for cloud-cloud collision as a major mechanism of high-mass star formation in the Carina-Sagittarius Arm., Comment: 13 pages, 7 figures, 3 tables, accepted for publication in PASJ

Aims Progranulin (PGRN) is a multifunctional protein known to be involved in inflammation. However, the relation between PGRN and atherosclerosis remains elusive. The aim of this study was to define the role of PGRN in the development of atherosclerosis. Methods and results First, we checked the expression levels of PGRN in human atherosclerotic plaques. Immunohistochemical analysis showed that PGRN is strongly expressed in foam cells of atherosclerotic plaques. We also found that PGRN is expressed more abundantly in macrophages than in the smooth muscle cells of atherosclerotic lesions in ApoE−/− mice fed a high-fat diet for 12 weeks. Next, PGRN−/−ApoE−/− mice were generated to investigate the effect of PGRN on the development of atherosclerosis. PGRN−/−ApoE−/− mice exhibited severe atherosclerotic lesions compared with PGRN+/+ApoE−/− mice, despite their anti-atherogenic lipid profile. These results are partly due to enhanced expression of inflammatory cytokines, adhesion molecules, and decreased expression of endothelial nitric oxide synthase. In addition, lack of PGRN leads to accumulate excessive cholesterol in the macrophages and alter HDL-associated proteins. Conclusion PGRN seems to be involved in the pathogenesis of atherosclerosis, possibly by various anti-atherogenic effects, including modulation of local and/or systemic inflammation.

We examined the protective effect of intratracheal immunization with Pseudomonas aeruginosa pili protein against respiratory infection caused by P. aeruginosa. Mice were immunized intratracheally or subcutaneously with purified pili protein or bovine serum albumin as a control. Intratracheally but not subcutaneously pili protein-immunized mice showed significant improvement of survival after intratracheal challenge with the PAO1 strain. Furthermore, bacterial cell counts in pili protein-immunized murine lungs were significantly decreased compared to controls at 18 h after the challenge. Antipili protein antibody titers in bronchoalveolar lavage fluid of intratracheally pili protein-immunized mice were higher than in bovine serum albumin immunized mice. However, antipili antibody titers were not increased in bronchoalveolar lavage fluid of subcutaneously pili protein-immunized mice, despite the high serum antipili antibody titers. Inoculation of P. aeruginosa induced immediate increases in interleukin-12 and interferon-gamma in bronchoalveolar lavage fluid of pili protein-immunized mice, reflecting an adequate and rapid immune response against P. aeruginosa respiratory tract infection. Our findings suggest that intratracheal pili protein immunization is effective against respiratory tract infection caused by P. aeruginosa in mice.

Sperm concentration and motility are poor predictors of the outcome of intrauterine insemination (IUI), hysteroscopic intratubal insemination (HIT), or complete fertilization failure (CFF) in conventional IVF. We investigated whether the calcium ionophore-induced acrosome reaction (AR) constitutes an additional indicator of CFF and pregnancy that is independent of these semen parameters.Infertile couples with no female factor (n=388) and women with tubal obstruction (n=32) were studied: IVF (n=133), ICSI (n=72), HIT (n=245) and IUI (n=61). The percentage of acrosome-reacted sperm in relation to viable sperm was calculated. Receiver operating characteristic curve and multiple logistic regression analyses were used to determine threshold values and the best predictor for CFF and pregnancy.Threshold values of AR for predicting CFF in IVF and pregnancy in IVF and HIT + IUI were 21, 26 and 22% respectively. These values were independent of the conventional semen analysis parameters. CFF was lower (2 versus 20%; P0.01) and the pregnancy rate was higher (46 versus 24% P0.05) for those with AR21% in IVF. CFF and pregnancy rate in ICSI did not differ according to AR. Pregnancy rate was higher for those with an AR22% for HIT + IUI (23 versus 11% P0.01).Ionophore-induced AR appears to be a useful indicator in addition to routine semen analysis for selection of patients for treatment with appropriate assisted reproduction procedure.